Transition Metal-Free sp3 C–H Functionalization of Arylacetic Acids for the Synthesis of 1,3,5-Triazines

Article abstract of DOI:10.1002/ejoc.201800178

A one-pot simple, efficient and practically viable protocol for the synthesis of substituted 1,3,5-triazines has been reported from arylacetic acids and benzamidine hydrochloride. In addition, we demonstrated first transition metal-free conversion of phenylacetic acid to benzaldehyde which on condensation with two equivalents of benzamidine hydrochloride offered 2,4,6-trisubstituted 1,3,5-triazines. This protocol is environmentally benign and economically viable which makes it feasible for gram scale synthesis.

Full text of DOI:10.1002/ejoc.201800178

A Journal of
Accepted Article
Title: Transition Metal-Free sp3 C-H Functionalization of Arylacetic
Acids for the Synthesis of 1,3,5-Triazines
Authors: Atul Chaskar, Sachin Pardeshi, Pratima Sathe, Balu Pawar,
and Kamlesh Vadagaonkar
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800178
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800178
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European Journal of Organic Chemistry
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COMMUNICATION
3
Transition Metal-Free sp C-H Functionalization of Arylacetic Acids
for the Synthesis of 1,3,5-Triazines
[
a]
[a]
[b]
[c]
Sachin D. Pardeshi, Pratima A. Sathe, Balu V. Pawar, Kamlesh S. Vadagaonkar, * and Atul C.
Chaskar *
[
a]
Abstract: A one-pot simple, efficient and practically viable protocol
for the synthesis of substituted 1,3,5-triazines has been reported from
arylacetic acids and benzamidine hydrochloride. In addition, we
demonstrated first transition metal free conversion of phenylacetic
acid to benzaldehyde which on condensation with two moles of
benzamidine hydrochloride offered 2,4,6-trisubstituted 1,3,5-triazines.
This protocol is environmentally benign and economically viable which
makes it feasible for gram scale synthesis.
2,3-dialkyl-1,4-dilithio-1,3-dienes with nitriles in the presence of
hexamethylphosphoramide (HMPA) while recently Majumdar et
al. synthesized 1,3,5-triazines through copper-catalyzed
cyclization of N-benzylbenzamidines in DMSO.[15] 2,4,6-
Triphenyl-1,3,5-triazine have also been synthesized via oxidative
cyclization of benzamidine hydrochloride with benzoyl
isothiocyanate, benzaldehyde,[17] benzyl alcohol,[18] toluene,
etc. (Figure 1). Jiang et al. used copper catalyst along with K PO
and O as the oxidant through single-electron-transfer (SET)
[
16]
[19]
3
4
2
[
20]
mechanism
whereas Bhanage et al. utilized PEG-600 in
DMSO[ and Cs
21]
CO
in TBHP
[22]
for the synthesis of 1,3,5-
Introduction
2
3
triazines from benzylamines and styrenes, respectively.
Nevertheless, these methods are associated with few
shortcomings such as requirement of halogenated substrate,
production of stoichiometric amount of undesirable waste,
requirement of excess amines as co-catalyst, oxidation of
aldehyde under normal environment and its decarboxylation at
harsh reaction conditions. The C-H functionalization/activation
received enormous attention in recent years due to their potential
applications in synthesis of heterocyclic motiefs via selective
construction of new C-C and C-heteroatom bonds. Indeed, its
mechanistic understanding led to development of novel
economically and environmentally benign synthetic protocols.
These matter of facts and our ongoing work[23] on the
development of transition-metal free economically viable
protocols for organic synthesis motivated us to use arylacetic
acids as readily available stable starting material and potassium
carbonate as inexpensive base which would lead to the
development of scalable process for synthesis of aryl substituted
1,3,5-triazines
Heterocyclic compounds in general nitrogen heterocycles are
incredibly diverse and received enormous attention over the past
many decades owing to their promising potential applications.
Indeed, among them 1,3,5-triazine moiety is widely explored as it
is a part of many natural products and demonstrated broad
[
1]
spectrum of biological and medicinal activities viz antibacterial,
[
2]
[3]
[4]
anti-inflammatory, antimalarial, antituberculosis, antitumor
agents[5] and inhibition of photosynthetic electron transport and
binding.[6] Albeit, their unique properties made them useful as
chelating ligands,[7] liquid crystals,[8] hydrogenation catalysis,[9]
and Optical properties.[10]
These enormous significant applications have
attracted the research community towards development of simple
and economically viable methods for synthesis of 1,3,5-triazines.
In last few years there are various methods have been developed
by many researchers across the globe for the synthesis of 1,3,5-
triazines. Many reports were found for the synthesis of 1,3,5-
triazines which involve cyclotrimerization of nitriles.[11] In 1985,
Saa et. al. used Fremy’s salts with aromatic aldehydes for the
synthesis of aryl-substituted s-triazines.[12] Xi and co-workers
reported synthesis[13] and mechanistic studies[14] of triazines using
[
a]
S. D. Pardeshi, P. A. Sathe, A. C. Chaskar
National Centre for Nanosciences and Nanotechnology, University
of Mumbai, Mumbai 400098, India
E-mail: achaskar25@gmail.com
[
b]
c]
B. V. Pawar
Arts, Commerce and Science College, Jawhar, Dist.: Palghar
K. S. Vadagaonkar
[
Department of Dyestuff Technology, Institute of Chemical
Technology, Mumbai 400019, India
E-mail: vadgaonkarks@gmail.com
Supporting information for this article is given via a link at the end of
the document.
Figure 1. Methods for the synthesis of substituted triazines.
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European Journal of Organic Chemistry
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COMMUNICATION
Results and Discussion
Table 2. Scope of various arylacetic acids for the synthesis of 1,3,5-
triazines.[
a]
Table 1. Optimization of Reaction Conditions.[a]
Entry
Base
Cs CO
Na CO
CH COONa
CO
Solvent[e]
DMF
Yield [%][b]
1
2
3
4
5
6
7
8
9
2
3
84
2
3
DMF
82
3
DMF
85
K
2
3
DMF
94
K
K
K
K
K
K
K
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
DMSO
DPE
83
78
Xylene
Toluene
DMA
n.d.
n.d.
n.d.
21
1
0
1
TBHP
DMF
1
32[c] /61[d]
[
a] Reaction conditions: phenylacetic acid 1a (1.0 mmol), benzamidine
hydrochloride 2a (2.0 mmol), base (2.0 mmol), solvent (2.0 mL) were heated
o
at 120 C for 4 h. [b] Yield of isolated product after column chromatography.
c] Reaction performed at 90 C. [d] Reaction performed at 100 oC. [e]
o
[
Abbrevations: DPE = diphenyl ether, DMA = dimethylacetamide, TBHP =
tert-butyl hydroperoxide
[
a] Reaction conditions: arylacetic acid 1 (1.0 mmol), substituted
benzamidine hydrochloride 2 (2.0 mmol), base (2.0 mmol), solvent (2.0 mL)
were heated at 120 C for 4-8 h.
o
At the outset we began our investigation by exploring the
model reaction of phenylacetic acid 1a with benzamidine
hydrochloride 2a in basic medium. Substantially good yields of
The scope and limitations of this method were explored by
performing the reaction of various arylacetic acids 1 with
benzamidine hydrochloride 2a under the optimized reaction
conditions (Table 2). Phenylacetic acid 1a on reaction with
benzamidine hydrochloride 2a afforded 2,4,6-triphenyl-1,3,5-
triazine 3aa in 94% yield. Arylacetic acids bearing halogen
substituents (2-Cl, 3-Cl, 4-Cl, 2,4-dichloro, 4-Br and 3-F) gave
corresponding products 3ab-3ag in good to excellent yields (75-
3%). Similarly, arylacetic acids with electron-donating
substituents (4-CH 4-OMe, 2-OH and 3-OPh) produced
respective 2,4,6-trisubstituted-1,3,5-triazines 3ah-3ak in good
yields (76-92%) while arylacetic acids bearing
withdrawing substituents such as 4-CF and 4-NO
1
,3,5-triazine 3aa was observed in the presence of base (2.0
equiv.) like Cs CO , Na CO as well as NaOAc in N,N-dimethyl
formamide (Table 1, entries 1-3). Notably, a highest yield of 94%
was noticed in the presence of K CO in DMF (Table 1, entry 4).
2
3
2
3
2
3
Looking at the scope for improvement in the yield, screening of
solvents was carried out. The reaction in DMSO and DPE offered
,3,5-Triazine 3aa in 83% and 78% yields, respectively (Table 1,
entries 5 and 6). However, the reaction did not take place in the
presence of xylene, toluene and N,N-dimethylacetamide (Table 1,
entries 7-9) while, a very low yield of 21% was observed in TBHP
8
1
3
,
electron-
3
2
furnished the
(
4.0 equiv.) (Table 1, entry 10). Next, we studied the effect of
respective triazines 3al and 3am in 78% and 73% yields,
respectively.
To extend the scope of the reaction, we next screened
heteroarylacetic acids such as (2-(thiophen-2-yl)acetic acid and
temperature on this reaction and found it detrimental as lower
yields of product were obtained on decreasing the temperature
(
o
o
61% and 32% at 100 C and 90 C, respectively) (Table 1, entry
1).
2-(1H-pyrrol-2-yl)acetic acid and as expected these acids offered
1
corresponding triazines 3an and 3ao in 63% and 67% yields,
respectively under the optimized reaction conditions. We found
that this method is robust and can tolerate various functional
groups. This implies that the above mentioned protocol could be
successfully applied for the large scale synthesis of various 1,3,5-
triazines from diverse aryl/hetero acetic acids. In view of the broad
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European Journal of Organic Chemistry
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COMMUNICATION
substrate scope, the present method was evaluated for the gram
scale synthesis of 2,4,6-triphenyl-1,3,5-triazine. Gratifyingly, 1 g
of phenylacetic acid produced 0.63 g of 2,4,6-triphenyl-1,3,5-
triazine with a yield of 94% under the optimized reaction
conditions. Thus, this protocol can be applied for the gram scale
synthesis of 2,4,6-triphenyl-1,3,5-triazine.
Experimental Section
The scope of this reaction was extended by employing
substituted benzamidine hydrochloride with phenylacetic acid.
Phenylacetic acid 1a on reaction with 4-methyl substituted
benzamidine hydrochloride afforded corresponding product 3ap
in 74 % yield in 8 h.The reaction of phenylacetic acid 1a with 4-
bromobenzamidine hydrochloride occured smoothly to give
corresponding product 3aq in 71% yield in 8 h.
General Experimental Procedure for the Synthesis of 1,3,5-
triazines
A round-bottom flask equipped with a magnetic stirring bar was
charged with arylacetic acid (1) (1.0 mmol), K
2
CO
2.0 mL) at room temperature. Substituted benzamidine hydrochloride (2)
2.0 mmol) was added to this mixture and the resulting mixture was heated
3
(2.0 mmol) and DMF
(
(
o
at 120 C for 4 to 8 h. The reaction progress was monitored by using TLC.
After completion of the reaction, water was added to the reaction mixture
and the aqueous layer was extracted with ethyl acetate (10 mLx3). The
To gain more insight on the role of K
hypothesis, a couple of control experiments were conducted
Scheme 1). Initially, when a mixture of phenylacetic acid (1a) and
2 3
CO and endorse our
(
2 4
organic layer was dried over anhydrous Na SO and concentrated under
o
reduced pressure. The residue obtained was purified by column
chromatography on 60-120 mesh silica gel by using n-hexane:ethyl
acetate (9:1) as the eluent to afford 2,4,6-trisubstituted-1,3,5-triazine (3).
2 3
K CO was heated in DMF at 120 C for 12 h, 98 % conversion to
benzaldehyde (A) was observed (Scheme 1, a). But, when the
reaction of phenylacetic acid (1a) with benzamidine hydrochloride
(
2a) was performed in the presence of K
2 3
CO , it went to
completion in only, this implied that benzamidine
4
h
hydrochloride (2a) playing a key role in accelerating the rate of
reaction (Scheme 1, b).
Acknowledgements
S.D.P thanks Department of Science and Technology, New Delhi,
India for providing a DST-PURSE fellowship. K.S.V. and A.C.C.
thanks DST-SERB, India (sanction no. SB/FT/CS-147/2013) for
financial support. Authors thank Prof. A. K. Srivastava, Former
Director, National Centre for Nanosciences and Nanotechnology,
University of Mumbai for his generous support. Authors gratefully
acknowledge V.N.K., S.C.K. and Organic Research Laboratory,
Department of Chemistry, University of Mumbai for their generous
help and support.
Scheme 1. Control Experiments
On the basis of control experiments a plausible mechanism
is depicted in Scheme 2. Initially, arylacetic acid (1) in the
2 3
presence of K CO undergoes oxidative decarboxylation to give
3
aromatic aldehyde [A] which reacts with benzamidine
hydrochloride (2a) and forms shiff base [B]. Intermediate [B]
undergoes conjugate addition reaction with another molecule of
benzamidine hydrochloride (2a) to give [C] which on oxidation
offers desired product 1,3,5-triazine (3).
Keywords: Arylacetic acid • Benzamidine hydrochloride • K
C-H Functionalization • Transition metal-free
2 3
CO • sp
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Key Topic*
a
a
Sachin D. Pardeshi, Pratima A. Sathe,
Balu V. Pawar,[ Kamlesh S.
b]
Vadagaonkar, [c]* and Atul C. Chaskar [a]*
Page No. – Page No.
An efficient transition metal-free protocol for the synthesis of 1,3,5-trisubstituted
triazines has been developed through C-H functionalization of arylacetic acids by
using K CO as a base, followed by condensation with substituted benzamidine
2 3
Title
3
Transition Metal-Free sp C-H
Functionalization of Arylacetic Acids
for the Synthesis of 1,3,5-Triazines
hydrochloride.
*Transition metal-free, C-H Functionalization
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